Interleukin-6 (IL-6) is a cytokine that is produced in response to various stimulators and is responsible for a variety of biological activities, including the stimulation of B- and T-cell growth and differentiation (Muraguchi et al., J. Exp. Med. 167: 332 (1988)), production of acute-phase proteins in response to inflammation or tissue injury (Gauldie et al., PNAS USA 84: 7251 (1987); Geiger et al., Eur. J. Immunol. 18: 717 (1988)), multilineage hematopoiesis, osteoclast formation, maturation of megakaryocytes, and platelet production. These biological activities are initiated when IL-6 binds to the extracellular portion of the interleukin-6 receptor, which is variously referred to as the interleukin-6 a subunit (IL-6Rα) or B-cell stimulating factor receptor (BSF-2 receptor). When IL-6 binds to IL-6Rα, a complex is formed. The complex then binds to the extracellular portion of the interleukin-6 receptor known as gp130, which is also referred to as the interleukin-6β subunit (IL-6Rβ). The resulting complex then transmits the IL-6 signal intracellularly.
The precursor of the IL-6 receptor reportedly comprises 468 amino acids (Yamasaki et al., Science 241: 825–828 (1988)). The mature IL-6 receptor reportedly comprises 449 amino acids (Yamasaki et al. (1988), supra).
Abnormal expression of IL-6 has been implicated in the pathogenesis of a variety of diseases, including multiple myeloma, plasmacytoma, hematological diseases such as plasma cell dyscrasias, leukemia and lymphoma (including non-Hodgkins's lymphoma and Lennert's T-cell lymphoma (Kishimoto, Blood 74: 1 (1989)), mesangial proliferative glomerulonephritis, polyclonal B-cell activation conditions, allergic diseases (Type I–IV), rheumatoid arthritis (Hirano et al., Eur. J. Immunol. 18: 1797 (1988)), diabetes, multiple sclerosis, SLE, septic shock, bacterial infection, viral infection, post-menopausal osteoporosis, chronic immune deficiency and autoimmune diseases (Med. Immunol. 15: 195–201 (1988)), including organ-specific and systemic diseases and AIDS, inflammatory diseases, and Cattleman's disease. In addition, IL-6 production has been associated with cardiac myxoma and cervical cancer (Kishimoto et al., Ann. Rev. Immunol. 6: 485 (1988)) in vivo and myelomas, histiocytomas and promyelocytic leukemia (Taga et al., J. Exp. Med. 166: 967 (1987)) in vitro. Attempts to abrogate the effects of abnormal expression of IL-6 can be made at its site of production or at its target.
In view of the above, there remains a need for materials and methods for identifying and designing agents that inhibit IL-signaling and for treating diseases involving IL-6 signaling prophylactically and therapeutically. It is an object of the present invention to provide such materials and methods. This and other objects and advantages, as well as additional inventive features, will become apparent from the detailed description provided herein.